Evaluation of Safety and Efficacy of CRN04894 in Patients with Congenital Adrenal Hyperplasia: An Open-Label, Long-Term Extension Study
- Trial ID
- 2024-514846-35-00
- Protocol
- CRN04894-09
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of CRN04894 in participants with **Congenital Adrenal Hyperplasia**. Additionally, the primary efficacy objective is to assess the efficacy of CRN04894 by measuring the change from baseline in serum **androstenedione** (A4) levels. This is clinically relevant as it aims to determine the potential of CRN04894 to manage hormone levels in this condition, which is crucial for improving patient outcomes.
Secondary efficacy objectives include evaluating the efficacy of CRN04894 by measuring the change from baseline in serum **17-hydroxyprogesterone** (17-OHP) levels and assessing the need for **glucocorticoid** (GC) therapy. These secondary objectives are important for understanding the broader impact of CRN04894 on hormone regulation and the potential reduction in glucocorticoid dependency, which can have significant implications for the long-term management of Congenital Adrenal Hyperplasia.
Participants
The clinical trial involves a total of **148 participants** diagnosed with **congenital adrenal hyperplasia**. The study population includes both male and female subjects, with an age range that encompasses adolescents and adults. Participants were selected based on their completion of a prior Crinetics CRN04894 study, with an acceptable benefit-risk assessment, and are compliant with a stable regimen of glucocorticoid replacement therapy. The trial includes individuals who are considered part of a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if applicable. The selection criteria ensure that participants are willing and able to comply with study procedures and provide informed consent.
Plans and Procedures
The clinical trial is designed as an **open-label**, long-term extension study to evaluate the safety and efficacy of the investigational drug CRN04894 in participants with **congenital adrenal hyperplasia** (CAH). The trial is categorized as a Phase 4 study and is not considered low intervention. The primary objective is to assess the safety and tolerability of CRN04894, with efficacy measured by changes from baseline in serum androstenedione (A4). The trial will also monitor secondary efficacy endpoints, including changes in serum 17-hydroxyprogesterone (17-OHP) and daily glucocorticoid (GC) dose over time.
Participants eligible for this study are those who have completed a previous CRN04894 study and are deemed by the investigator to have an acceptable benefit-risk assessment. The study will involve oral administration of CRN04894 in tablet form, with a maximum daily dose of 120 mg and a total treatment period not exceeding 104 weeks. The trial is expected to commence recruitment on February 28, 2025, and conclude by November 30, 2027.
The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria, such as compliance with a stable glucocorticoid regimen and appropriate contraceptive measures for participants of childbearing potential. Follow-up visits will be scheduled to monitor safety endpoints, including the incidence of treatment-emergent adverse events (TEAEs) and any adverse events leading to discontinuation. The end-of-study visit will assess the overall safety and efficacy outcomes.
Participant involvement is expected to last up to 104 weeks, with conditions for early termination including the occurrence of serious adverse events or non-compliance with study procedures. The study aims to provide comprehensive data on the long-term use of CRN04894 in managing CAH, contributing valuable insights into its safety profile and therapeutic efficacy.
Treatment
The clinical trial involves the administration of the **experimental medication** CRN04894, which is an ACTH receptor antagonist. This medication is provided in the form of a **tablet** and is intended for **oral** administration. The maximum daily dose of CRN04894 is 120 mg, with a total maximum dose of 87.36 g over the course of the study. The treatment period extends up to 104 weeks. CRN04894 is a chemical product developed by Crinetics Pharmaceuticals, Inc., and is not formulated for pediatric use. The primary objective of the trial is to evaluate the safety and efficacy of CRN04894, specifically by measuring changes in serum androstenedione (A4) levels from baseline.
In addition to the experimental treatment, the study may include the use of **non-experimental treatments** such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. These treatments are used to provide a baseline for comparison and to ensure the safety and well-being of participants. The administration of these treatments will follow standard medical guidelines and will be monitored for compliance throughout the study duration.
Participant compliance with the dosing schedule will be closely monitored to ensure adherence to the prescribed regimen. This will involve regular assessments and documentation of medication intake, as well as any adverse events or deviations from the protocol. The study aims to maintain high standards of data integrity and participant safety through rigorous monitoring and reporting procedures.
Efficacy
The efficacy of CRN04894 in the clinical trial will be assessed primarily by measuring the change from baseline in morning (before 11:00 AM) serum **androstenedione (A4)** levels over time. This primary efficacy endpoint is designed to evaluate the impact of the treatment on serum A4, a key biomarker associated with the condition under study. Secondary efficacy endpoints include the change from baseline in morning serum 17-hydroxyprogesterone (17-OHP) levels over time and the change from baseline in daily glucocorticoid (GC) dose, measured in hydrocortisone (HC) milligram equivalents, over time.
The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the study. The measurements will be taken in the morning before 11:00 AM to ensure consistency and reliability of the data. The study will utilize validated laboratory tests to quantify serum A4 and 17-OHP levels, ensuring the accuracy and precision of the efficacy assessments. The data collected will be analyzed to determine the efficacy of CRN04894 in achieving the desired changes in these biomarkers, which are indicative of the therapeutic effect of the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants with CAH who have completed the Treatment Period in a Crinetics parent atumelnant CAH study and in the opinion of the Investigator had an acceptable benefit-risk assessment in the completed study and would benefit from continued dosing in this extension study: a. Group 1: Participants meeting the above criteria and did not have study drug administration interrupted between EOT of the parent study and the commencement of the OLE study. b. Group 2: Participants meeting the above criteria but had study drug administration interrupted between EOT of the parent study and the commencement of the OLE study. Note: The maximum dose of atumelnant in this study is 120 mg QD.
- Female participants who engage in heterosexual intercourse must: a. Be of nonchildbearing potential, defined as either surgically sterile (ie, hysterectomy or bilateral salpingectomy for at least 3 months, or bilateral oophorectomy), OR b. Be postmenopausal with at least 1 year of amenorrhea. In participants with less than 1 year of amenorrhea, confirmation is required with 2 follicle-stimulating hormone (FSH) measurements. A documented, historical test result measured prior to Screening may be used as 1 of the 2 measurements. The FSH value should be ≥30 IU/L to confirm menopausal status, OR c. Agree to use a highly effective method of contraception from the beginning of Screening until at least 2 weeks after the last dose of study drug. Contraceptive use by men and women also should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Periodic abstinence (ie, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Note: For further information about contraception, see Section 11.3 for details.
- Male participants agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 2 weeks after the last dose of study drug (or be surgically sterile [ie, vasectomy with a confirmed absence of sperm in ejaculate]; or agree to remain abstinent on a long-term and persistent basis). Male participants should also agree to not donate sperm for the duration of the study and until at least 2 weeks after the last dose of study drug. Note: For further information about contraception, see Section 11.3 for details.
- Participants are willing and able to give signed informed consent, including compliance with the requirements and restrictions listed in the Informed Consent Form (ICF).
- Participants are willing and able to comply with the study procedures as specified in the protocol and comply with the study treatment.
Exclusion Criteria
- The following exclusion criteria apply to all participants (Group 1 and Group 2): 1. Any medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardize the participant’s safety or ability to complete the study.
- Participants have known history of (that is within the past 12 months), or current alcohol or drug abuse.
- Participants have any mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study, and/or evidence of poor compliance with medical instructions.
- Participants have a known allergy or hypersensitivity to any of the test materials or related compounds, including being at high risk of adrenal insufficiency as judged by the Investigator.
- Women who are pregnant or lactating or, if of childbearing potential, who are unwilling to use highly effective contraception as described in this study. Male participants who are unwilling to use highly effective contraception as described in this study.
- Participant is an employee or immediate family member of an employee of Crinetics.
- Participants who have been dosed with an investigational drug (other than atumelnant) in any prior clinical study within 60 days or 5 half-lives (whichever is longer) prior to informed consent or plan to use an investigational drug in another study.
- Participants who have had an active malignant disease within the last 5 years prior to Screening excluding dermal squamous or basal cell carcinoma of the skin with complete local excision or resected cervical carcinoma in situ.
- Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- The following additional exclusion criteria apply to participants in Group 2 only (Screening required): 10. Participants with any clinically significant abnormal laboratory test during Screening or clinically significant concomitant disease other than CAH including but not limited to cardiovascular disease; moderate or severe renal insufficiency (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 using Chronic Kidney Epidemiology Collaboration [CKD-EPI] formula) at Screening; or Significant liver disease or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3× upper limit of normal (ULN), and/or total bilirubin >1.5×ULN during Screening. Participants with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and associated with total bilirubin <3.5 mg/dL (<51.3 μmol/L) will be permitted.
- Participants with a history of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic GC therapy.
- Participants with a history of major surgery/surgical therapy for any cause within 4 weeks prior to Screening.
- Participants with poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) ≥8.5% (≥69 mmol/mL).
- Participants with hypothyroidism who are not receiving adequate hormone replacement therapy based on thyroid hormone levels measured at the time of Screening, as determined by the Investigator.
- Participant has an average (of 3 electrocardiograms [ECGs]) Fridericia’s corrected QT (QTcF) interval >450 milliseconds (msec) (men) or >470 msec (women), time interval between P and R waves (PR interval) >220 msec, time interval of the QRS complex (QRS) interval >120 msec, second- or third-degree atrioventricular block, left bundle branch block, or hemiblock at Screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 28 Feb 2025 | 1 |
 Italy | Recruiting | 28 Feb 2025 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Atumelnant 80 mg tablets | Test | TABLET | ORAL | 120 | 104 | PRD12509627 |
Atumelnant 120 mg tablets | Test | TABLET | ORAL | 120 | 104 | PRD12509628 |
Atumelnant 40 mg tablet | Test | TABLET | ORAL | 120 | 104 | PRD10377546 |